Alzheimer's disease (AD) is a devastating neurological disease that affects millions of people across the globe. The pathology of this disease is characterized by the accumulation of the beta amyloid (A?) protein into extracellular plaques and the intracellular accumulation of the microtubule associated protein tau. Inflammation has also been shown to play an important role in pathology, a theory supported by the recent discovery of mutations in the immune regulating protein TREM2 in AD patients. While it is known that TREM2 is important in suppressing inflammation and promoting phagocytosis, its exact role in AD is unclear. Our preliminary data suggests that TREM2 binds to Hsp60, a pro-inflammatory immune regulator that is increased in response to cellular stress. Because of their opposing actions on inflammation, we predict that Hsp60 biases TREM2 to interact with downstream components that block its anti-inflammatory function. We also show that Hsp60 levels are increased in neurons containing elevated levels of intraneuronal A? in a mouse model of AD. We predict that Hsp60 downregulates TREM2 activity in areas where cellular stress is high, thereby promoting inflammation at the specific time and in the specific location where cellular stress is occurring. Without TREM2, we predict that the balance in inflammation will tip toward proinflammatory responses and that inflammation will no longer be localized to areas of cellular stress. In order to determine the role of TREM2 in AD, we will first examine the role of Hsp60-TREM2 signaling in vitro. Using microglia cultured from WT or transgenic mice lacking TREM2, we will be able to determine the TREM2-dependent effects of Hsp60 treatment on cytokine production using qRT-PCR and phagocytosis, using a fluorescent microsphere uptake assay coupled with flow cytometry. We also aim to determine the changes in TREM2 and Hsp60 expression and localization during the progression of pathology in the 5xFAD AD mouse model using immunohistochemistry, Western blotting, and flow cytometry. We expect that expression of Hsp60 will increase in neurons early in pathology, and that TREM2 will be upregulated globally to re-set the balance of inflammation. Finally, we will look at the effect of the constitutive loss of TREM2 on pathology in AD mice. We expect that these mice will have increased production of pro- inflammatory cytokines and decreased phagocytic capacity. Consequently, when pathology in these mice is determined using ThioS staining for plaque number, and NeuN staining to assay neuronal loss, TREM2-/- 5xFAD mice will show earlier and more severe changes. We also predict earlier cognitive decline in AD mice which lack TREM2 in tests such as novel object recognition, radial arm water maze and fear conditioning. Through these studies, we hope to gain a better understanding of the role of TREM2 in AD and provide a novel avenue for the development of therapeutic interventions for AD patients.